A Prospective Study of Serotonin Transporter Gene Promoter
(5-HTT Gene Linked Polymorphic Region) and Intron 2
(Variable Number of Tandem Repeats) Polymorphisms
as Predictors of Trauma Response to Mild Physical Injury
Aslihan Sayin,1Sibel Kucukyildirim,2Taner Akar,3Zekiye Bakkaloglu,2Ahmet Demircan,4
Gulhan Kurtoglu,4Birol Demirel,3Selcuk Candansayar,1and Hatice Mergen2
The aim of this study was to examine the effect of both promoter and intron polymorphisms of the serotonin
transporter (5HTT) gene on posttraumatic stress disorder (PTSD) development. For this purpose, two poly-
morphisms of the 5-HTT gene, which are found in the promoter (5-HTT gene-linked polymorphic region) and
second intron (variable number of tandem repeats) of the gene, were analyzed in 100 patients who were
admitted to the Emergency Department after a mild physical trauma. None of the 5-HTT polymorphisms
studied have an effect on PTSD development after a mild physical injury, but having L allele for 5-HTT gene-
linked polymorphic region may cause milder hyperarousal symptoms in those patients who have developed
and diminished quality of life above and beyond the impact
of injury severity and medical comorbidity (Zatzick et al.,
2002). Given that 50–70% of individuals have been exposed
to at least one potentially traumatic event during their life-
time (Kessler et al., 1995; Breslau et al., 1998) and 10–40% may
develop high levels of PTSD symptoms after traumatic
physical injury (Blanchard et al., 1996; Michaels et al., 1999;
Ursano et al., 1999), early intervention and treatment of PTSD
has become an important component of public health efforts
targeting injury control and rehabilitation.
Molecular genetic studies have the potential to identify the
markers of vulnerability or resilience of pathological response
to trauma. To date, there are seven case–control candidate
gene association studies of PTSD (Nugent et al., 2008). Five of
them have focused on genes of dopamine system such as
dopamine receptor 2 (Comings et al., 1991, 1996; Gelernter
et al., 1999; Young et al., 2002) and dopamine transporter
(Segman et al., 2002), of which four found significant associ-
ation. Two studies have focused on serotonin system (Lee
et al., 2005; Kilpatrick et al., 2007) and both of them found
significant association between S=S genotype of serotonin
transporter promoter polymorphism and PTSD.
osttraumatic stress disorder (PTSD) is a disabling
psychiatric disorder that causes functional limitations
Although most of these molecular genetic studies have
focused on dopaminergic system, there are many reasons
to think that serotonergic system may be involved in the
susceptibility to PTSD. Evidence for an involvement of
serotonergic system in trauma response comes from both
neurobiological (Broekman et al., 2007; Weiss, 2007) and
clinical studies (Ipser et al., 2006; Opler et al., 2006).
Serotonergic neurotransmission is controlled by two main
mechanisms: synthesis of the transmitter regulated by the
rate-limiting tryptophan hydroxylase and termination of
transmission by serotonin transporter (5HTT). The magni-
tude and duration of serotonergic neurotransmission is de-
termined by the synaptic action of 5HTT (Lin and Tsai, 2004).
The 5HTT protein is encoded by a single gene, located on
chromosome 17q11.1–q12 (Lesch et al., 1994). The 5HTT gene
has two polymorphic regions with functional consequences.
The first polymorphism, which is observed in the 5-HTT
gene-linked polymorphic region (5-HTTLPR), is a 44-base
pair insertion (L allele) or deletion (S allele) in the 50regu-
latory promoter region. Long (L) and short (S) variants of the
promoter polymorphism differentially modulate transcrip-
tion of the 5HTT gene, with the S variant being less efficient
(Heils et al., 1996). The second polymorphism is a 17-base
pair variable number of tandem repeats (VNTR) in the sec-
ond intron of the gene, which may act as a transcriptional
regulator, with 12-repeat allele having stronger enhancer-like
1Department of Psychiatry, Faculty of Medicine, Gazi University, Ankara, Turkey.
2Department of Molecular Biology, Faculty of Science, Hacettepe University, Ankara, Turkey.
Departments of3Forensic Medicine and4Emergency, Faculty of Medicine, Gazi University, Ankara, Turkey.
DNA AND CELL BIOLOGY
Volume 29, Number 2, 2010
ª Mary Ann Liebert, Inc.
properties than 10-repeat allele (Ohara et al., 1998; MacK-
enzie and Quinn, 1999).
There are only two studies about the influence of the 5-
HTT gene on susceptibility to PTSD, and both of them have
examined only the 5-HTTLPR polymorphism. This study
examined the effect of both 5-HTTLPR and VNTR poly-
morphisms of the 5-HTT gene on PTSD development in a
population exposed to mild physical trauma. We hypothe-
sized that ‘‘lower activity’’ alleles (S in 5-HTTLPR and 10 in
VNTR) would be associated with higher frequency of PTSD
symptoms=full syndrome 6 months after exposure to phys-
Materials and Methods
This study was conducted by collaboration of the Emer-
gency, Forensic Medicine, and Psychiatry Departments of
Gazi University Hospital and the Molecular Biology De-
partment of Hacettepe University. This study was ethically
approved by the local Ethics Committee of the Medical
Faculty of Gazi University.
One hundred patients who have been consecutively ad-
mitted to the Adult Emergency Department of Gazi Uni-
versity Hospital because of a physical trauma (vehicle=
motorcycle accident, assault, stroke) were included in this
study. A written informed consent was obtained from each
patient. Systolic blood pressure (minimum–maximum, 80–
160; mean?standard deviation, 113.30?15.16mmHg), dia-
stolic blood pressure (50–100, 75.05?9.30mmHg), heart rate
(58–140, 91.17?18.25 beats=min), respiratory rate (12–24,
18.77?2.56 breaths=min), O2 saturation (94–100, 97.18?
0.97%), and Glasgow coma scale (14–15, 14.95?0.21) of each
patient was recorded and revised trauma score was calculat-
ed; patients who had a revised trauma score other than 7.841
were excluded from this study.
Sociodemographic information (age, gender, marital sta-
tus, education level, employment status), current and past
psychiatric disorders, family history of psychiatric disorder
(according to the information given by the patient and family
members=friends), and kind of trauma (vehicle=motor acci-
dent, assault, stroke) were recorded and peripheral venous
blood samples for genetic analysis were obtained by a phy-
sician (G.K.). Their telephone numbers were recorded and a
psychiatrist (A.S.), with 8 years clinical psychiatric experi-
ence, called them 6 months after their admission to the
Emergency Department (to include late onset PTSD cases as
well) and interviewed them using the clinician-administered
PTSD scale (CAPS).
Clinician-administered PTSD scale. This is a 17-item scale
used for the assessment of current and lifetime PTSD symp-
toms (Blake et al., 1995). The 17 symptoms cluster into three
subscales: CAPS-B for reexperience, CAPS-C for avoidance=
numbing, and CAPS-D for arousal. Each symptom is as-
sessed according to frequency and intensity, and rated on
a 0–4 scale. Any symptom is considered as positive, only if
the total score of frequency and intensity is at least 3. A
subject is diagnosed as having PTSD if there is at least one
reexperience, three avoidance, and two arousal symptoms. A
subject is considered positive for lifetime symptoms, if
he=she had the symptoms within a certain amount of time
after the traumatic event (the question was asked: Have you
ever had these symptoms at least 1 month after the trauma?).
A subject is considered positive for current symptoms if
he=she still has these symptoms (the question was asked:
Do you still have these symptoms?). The Turkish version
of CAPS has Cronbach alpha of 0.91 for the whole scale, 0.78
for reexperience symptoms, 0.78 for avoidance=numbing
symptom, and 0.82 for hyperarousal symptoms (Aker et al.,
Peripheral venous blood samples (5mL) were collected
from all subjects into ethylenediaminetetraacetic acid-treated
tubes and were preserved at þ48C. Genomic DNA was ex-
tracted from peripheral blood lymphocytes according to
standard phenol–chlorofom method. PCR for the 17-bp
VNTR and 44-bp insertion=deletion polymorphisms were
performed in total volumes of 25mL reaction mixture con-
taining 1?PCR Buffer (Bioron, Ludwigshafen, Germany),
10pmol of each primer, 10% dimethyl sulfoxide (DMSO),
200mM of each dNTP (Larova, Teltow, Germany), 10ng
DNA, and 1U Taq polymerase (Bioron).
For genotyping of the 44-bp insertion=deletion polymor-
phism, the 5-HTTLPR region was amplified using the
(forward) plus HTTLPR50-GGACCGCAAGGTGGGCGGGA-30
(reverse) (Steiger et al., 2007) which generates a 419- and 375-
bp product for the L and S alleles, respectively. The VNTR
region in the second intron of the 5HTT gene was amplified
using the primers 5-HTTVNTR50-GTCAGTATCACAGGCT
GCGAG-30(forward) plus HTTVNTR5-TGTTCCTAGTCT
TACGCCAGTG-30(reverse) (Li et al., 1997). The 5-HTT had
three alleles that were 250, 267, and 300bp and corresponded
to 9, 10, and 12 repeats, respectively. The PCR program for
both reactions consisted of one denaturing cycle at 948C for
3min, 35 cycles of 948C for 30s, 608C for 30s, 728C for 45s,
and final 5min extension at 728C. Amplification products
were electrophoresed on 2.5% agarose gel (Sigma–Aldrich,
Steinheim, Germany) and visualized with ultraviolet light
after ethidium bromide staining.
Statistical analysis of all the obtained data was made using
SPSS version 15.0 (SPSS Inc., Chicago, IL). Chi-square anal-
ysis was performed to find the statistical differences with
respect to all variables between patients with and without
lifetime PTSD according to CAPS scores. Kruskal–Wallis and
Mann–Whitney U tests were used to assess the association
between scores of CAPS subscales and sociodemographic
features, current and psychiatric history, family history of
psychiatric disorder, trauma subtype, both genotypes, and
four alleles in the patients with lifetime PTSD diagnosis. Ex-
ploratory analysis, including variables which were found to
have statistically significant effect on CAPS scores, was per-
72 SAYIN ET AL.
formed using multivariate linear regression analysis with
enter modeling. A p-value smaller than 0.05 was considered
Fourteen patients could not be reached by telephone after
6 months, and the blood samples of nine patients were unfit
for genetic analysis. This resulted in 77 patients for further
The patients were grouped according to their genotypes of
both polymorphisms; LL, SL, and SS for 5-HTTLPR poly-
morphism and 12.12, 12.10, and 10.10 for VNTR polymor-
phism. Moreover, they were also grouped with respect to the
existence of S and L alleles, as well as 12 and 10 alleles. For
the 5-HTTLPR polymorphism, the SL genotype was the most
frequently found one (60%, n¼54). About 24.4% (n¼22) of
the patients had the LL genotype and 15.6% (n¼14) had
the SS genotype. The L allele was more common than the
S allele, with a ratio of 3:1. For the VNTR polymorphism, the
12.12 genotype had the highest frequency of 58.9% (n¼53),
whereas the 10.10 genotype was second with 22.2% (n¼20)
and the 12.10 genotype was the most rarely found genotype
with 18.9% (n¼17). The 12 allele was more common than 10
allele, with a ratio of 3:1.
The results of CAPS scores of the patients who could be
reached by the telephone after 6 months were as follows:
when clinically significant positive symptoms were consid-
ered, 23.3% (n¼20) of the patients had current and 50.0%
(n¼43) had lifetime reexperiencing symptoms, 14.0% (n¼12)
of the patients had current and 32.6% (n¼28) had lifetime
avoidance symptoms, 15.1% (n¼13) of the patients had
current and 39.5% (n¼34) had lifetime hyperarousal symp-
toms, and 10.5% (n¼9) of the patients had current and 34.9%
(n¼30) had lifetime PTSD symptoms.
For further analysis, only lifetime PTSD was considered
because the number of patients with current PTSD was too
low for statistical analysis. Comparison of patients with and
without lifetime PTSD is summarized in Table 1.
Kruskal–Wallis and Mann–Whitney U tests were used to
find the possible variables that may have an effect on the
severity of PTSD symptoms in patients who had developed
PTSD. Gender, occupational status, marital status, psychiat-
ric history, as well as 5-HTTLPR and VNTR genotypes had
no significant association with scores from any of the PTSD
symptom clusters. Educational level (those with less than 8
years of education had significantly higher scores on lifetime
reexperiencing symptoms [mean¼3.59, p¼0.03], lifetime
[mean¼4.71, p¼0.04] and current [mean¼2.24, p¼0.04]
avoidance symptoms, lifetime [mean¼12.94, p¼0.01] and
current [mean¼6.65, p¼0.01] PTSD score), current psychi-
atric illness (those who did not have a current psychiatric
illness had significantly higher scores on lifetime reexper-
iencing symptoms [mean¼3.44, p¼0.01] and lifetime PTSD
[mean¼12.11, p¼0.03]), family history for psychiatric dis-
order (those who had a family history of psychiatric disorder
had significantly higher scores on current hyperarousal
symptoms [mean¼4.00, p¼0.01] and current PTSD [mean¼
12.33, p¼0.04]), and the type of trauma (those who had a
stroke had significantly higher levels of current reexperienc-
ing symptoms [mean¼2.00], current hyperarousal symptoms
[mean¼2.78, p¼0.01], and current PTSD [mean¼8.33,
p¼0.04]) were found to have a statistically significant effect
on the severity of PTSD symptoms and syndrome.
Comparison of mean scores of patients with lifetime PTSD
according to both genotypes and different alleles is presented
in Table 2.
A multivariate linear regression model was performed for
significant variables of symptom clusters of patients with
lifetime PTSD and the results are presented in Table 3.
We believe that there are three major findings in this
study. First, we did not find any significant association be-
tween development of PTSD and any of genotypes and al-
leles of both 5-HTT polymorphisms. The previous two
studies performed to investigate the association between 5-
HTLPR polymorphism and development of PTSD have both
found a significantly higher frequency of S allele in patients
with PTSD. The first one investigated 5-HTTLPR polymor-
phism in Korean patients with PTSD and normal controls
(control participants were not necessarily trauma exposed)
and found that the frequency of the S=S genotype was sig-
nificantly higher in patients with PTSD than in normal con-
trols (Lee et al., 2005). The second one used an epidemiologic
sampling strategy to examine whether 5-HTTLPR polymor-
phism moderated the risk of developing PTSD in 589 adults
exposed to the 2004 Florida hurricanes, and the authors
found that the S allele increased risk of posthurricane PTSD
only under the conditions of high hurricane exposure and
low social support (Kilpatrick et al., 2007). These studies did
not focus on VNTR polymorphism. The reasons for this
discrepancy between this and previous studies’ results may
be caused by the differences between sample characteristics
and instruments used to evaluate PTSD.
The second major result of this study was that both poly-
morphisms had a significant effect on the severity of some
specific symptoms in patients who had developed PTSD. The
‘‘higher activity’’ allele of 5-HTLPR polymorphism (L allele)
(Heils et al., 1996) caused significantly milder hyperarousal
symptoms, whereas the ‘‘higher activity’’ allele of the VNTR
polymorphism (12 allele) (Ohara et al., 1998; MacKenzie and
Quinn, 1999) was significantly associated with more severe
avoidance symptoms. Yet, one may assume that the de-
creasing effect of the L allele was stronger than the increasing
effect of the 12 allele, because the L allele kept its significance
even after the other variables were controlled.
The L allele’s effect was on severity of hyperarousal
symptoms. Key brain areas involved in hyperarousal re-
sponses are anterior cingulate cortex, medial prefrontal cor-
tex, amygdala, and thalamus (Lanius et al., 2006), which are
rich in serotonergic neurons. It has been proposed that the
failure of prefrontal cortex in its inhibition of stimuli from
reaching the amygdala may cause a hyperresponsive
amygdala, and an overactive amygdala may be responsible
for hyperarousal symptoms (Shin et al., 2006). Hypoactiva-
tion of these serotonergic neurons in the ascending serotonin
pathway, originating in the dorsal raphe nucleus and in-
nervating the amygdala and frontal cortex, caused by the
lower activity allele may result in more severe hyperarousal
symptoms, at least in this sample.
5-HTT POLYMORPHISM IN PTSD73
The third major result of this study was that having S allele
of the 5-HTTLPR polymorphism was significantly related to
more severe PTSD syndrome, although this significance was
lost after the other possible variables were controlled. The
result that the allele may cause lower activity of one of the
genes and regulate serotonergic neurotransmission, which
may be related to more severe PTSD symptoms, is impor-
tant because of the relationship between trauma response and
a hypoactive serotonergic system. Moderate stress causes se-
rotonin release to the frontal cortex and diminishes dysphoria
Table 1. Comparison of Patients with and without Lifetime Posttraumatic Stress Disorder
n (%) dfOR
Family history of PD
Variable number of tandem
aFisher exact test was performed.
bStatistically significant for p<0.05.
cAnxiety disorder (4), depression (3), undefined (2).
dAnxiety disorder (2), attention deficient hyperactivity disorder (1).
eUndefined (6), depression (2), schizophrenia (1).
fOR between first and second rows.
gOR between second and third rows.
hOR between first and third rows.
–=–, absence of SS and 10.10; –=þ, presence of SS or 10.10; PTSD, posttraumatic stress disorder; PD, psychiatric disorder.
1 0.203 10.4460.002a
1 0.7050.54 0.4
1 3.4811.119 0.5a
1 0.9920 1.0a
1 1.7820.978 0.4a
1 0.547 0.9220.3a
1 0.988 0.001 1.0a
74 SAYIN ET AL.
and anxiety (Bremner, 2006). However, severe stress or trau-
ma can lead to excessive serotonin activation in many regions
of brain (Kaehler et al., 2000) and cause serotonin depletion if
the trauma is chronic or becomes chronic by reexperiencing
symptoms and intrusive memories (Matsumoto et al., 2005).
Reduced availability of serotonin then leads to diminished
ability of the central nervous system to dampen emotional
responses to later stressors, increasing one’s proneness to
dysphoric states. Serotonin depletion may also contribute to
the symptoms of hyperarousal (e.g., hypervigilance, impul-
sivity, and irritability) that are seen in PTSD (Weiss, 2007).
Evidence of serotonin depletion in PTSD comes not only from
studies about beneficial treatment effects of serotonergic an-
tidepressants, but also from results of some neurobiological
studies, including decreased serum concentrations of seroto-
nin (Maes et al., 1999), decreased density of platelet serotonin
uptake sites (Spivak et al., 1999), and a blunted prolactin re-
sponse to d-fenfluramine (indicative of central serotonin hy-
poactivity) (Davis et al., 1999).
Our results need to be interpreted cautiously because they
come from a small sample and consists of people who were
exposed to only mild physical trauma. Diagnostic data for
PTSD were obtained from structured interviews over the
telephone rather than from in-person clinical interviews. In
addition, other psychiatric disorders, such as anxiety and
depression, which are also related to serotonergic system,
might have a significant effect on the development of PTSD
and we did not evaluate these disorders. Despite these lim-
itations, we believe that this study is of importance, because
to our knowledge this is the first study conducted in a pro-
spective design to investigate the VNTR polymorphism of
serotonin transporter gene as a predictor of trauma response,
and also the first study to investigate gene-by-environment
interaction in a Turkish population. However, our results
Table 2. Comparison of Mean Scores of Patients with Lifetime Posttraumatic Stress Disorder
According to Both Genotypes and Four Alleles
Variable number of tandem
LL SL SS12.12 12.110.1–=––=þ
RES, reexperiencing symptoms; AS, avoidance symptoms; HAS, hyperarousal symptoms; L, lifetime; C, current; –=–, absence of SS and
10.10; –=þ, presence of SS or 10.10.
Table 3. A Multivariate Linear Regression Model for Predictors of Severity of Current and Lifetime
Posttraumatic Stress Disorder Symptoms in Patients with Lifetime Posttraumatic Stress Disorder
Coefficient, b (significance, p)
RES-LRES-CAS-L AS-CHAS-L HAS-CPTSD-LPTSD-C
Education (>8, ?8)
Current PD (þ=–)
of PD (–=þ)
S allele (–=þ)
L allele (þ=–)
12 allele (–=þ)
(–=þ or –=–)
aStatistically significant for p<0.05.
b–, not included in multivariate linear regression model.
cStatistically significant for p<0.01.
VHA, vehicle accident; –=–, absence of SS and 10.10; –=þ, presence of SS or 10.10.
–0.34 (0.07)–––––0.32 (0.03)a
– 0.88 (0.38)
5-HTT POLYMORPHISM IN PTSD 75
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stated earlier, and further study is needed.
No competing financial interests exist.
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Address correspondence to:
Aslihan Sayin, M.D.
Department of Psychiatry
Gazi University Hospital
Besevler, 06500 Ankara
Received for publication June 26, 2009; received in revised
form September 3, 2009; accepted September 4, 2009.
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